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Although several drugs are available to treat recurrences of human epithelial ovarian cancer (EOC), clinical responses often remain short lived and lead to only marginal improvements in patients' survival. One of the new drugs proposed for recurrent platinum-resistant EOC patients is trabectedin (Trab), a marine-derived antitumor agent initially isolated from the tunicate Ecteinascidia turbinata and currently produced synthetically. Predictive biomarkers of therapy response to this drug and the potential use of non-invasive functional MRI and MRS approaches for an early assessment of Trab efficacy have not yet been evaluated, although they might be relevant for improving the clinical management of EOC patients. In the present work we combined functional and spectroscopic magnetic resonance technologies, such as in vivo diffusion-weighted MRI and 1 H MRS, with ex vivo high resolution MRS (HR-MRS) metabolomic analyses, with the aim of identifying new pharmacodynamic markers of Trab effectiveness on well characterized, highly aggressive human SKOV3.ip (a HER2-enriched cell variant derived from SKOV3 cells) EOC xenografts. In vivo treatment with Trab (three consecutive weekly 0.2 mg/kg i.v. injections) resulted in the following: (1) a significant reduction of in vivo tumor growth, along with the formation in cancer lesions of diffuse hyper-intense areas detected by T 2 -weighted MRI and attributed to necrosis, in agreement with histopathology findings; (2) significant increases in the apparent diffusion coefficient mean and median values versus saline-treated control tumors; and (3) a significant reduction in the choline-containing metabolites' signal detected by quantitative in vivo MRS. Multivariate and quantitative HR-MRS analyses on ex vivo tissue samples revealed Trab-induced alterations in phospholipid and glucose metabolism identified as a decrease in phosphocholine and an increase in lactate. Collectively, these data identify Trab-induced functional MRI and MRS alterations in EOC models as a possible basis for further developments of these non-invasive imaging methods to improve the clinical management of EOC patients., (© 2018 John Wiley & Sons, Ltd.)

Magnetic resonance imaging (MRI) and spectroscopy (MRS) offer powerful approaches for detecting physiological and metabolic alterations in malignancies and help investigate underlying molecular mechanisms. Research on epithelial ovarian carcinoma (EOC), the gynaecological malignancy with the highest death rate characterised by frequent relapse and onset of drug resistance, could benefit from application of these molecular imaging approaches. In this study, MRI/MRS were used to characterise solid tumour models obtained by subcutaneous (s.c.) or intraperitoneal (i.p.) implantation of human SKOV3.ip cells in severe combined immunodeficiency (SCID) mice. In vivo MRI/MRS, ex vivo magic-angle-spinning (MAS), and in vitro (1)H-NMR measurements were carried out at 4.7 T, 9.4 T, and 9.4/16.5 T, respectively. MRI evaluation was performed by T1-, T2-, and diffusion-weighted (DW) multislice spin-echo imaging. The in vivo (1)H spectra of all tumour models showed a prominent resonance of total choline-containing metabolites (tCho). Quantitative in vivo MRS of both i.p. and s.c. SKOV3.ip xenografts showed that the mean tCho content was in the 2.9-4.5 mM range, with a mean PCho/tCho ratio of 0.99 ± 0.01 [23 examinations, 14-34 days post injection (dpi)], in good agreement with ex vivo and in vitro analyses. Myo-inositol ranged between 11.7 and 17.0 mM, with a trend towards higher values in i.p. xenografts at 14-16 dpi. The average apparent diffusion coefficient (ADC) values of SKOV3.ip xenografts [1.64 ± 0.11 (n = 9, i.p.) and 1.58 ± 0.03 x10(-3) mm(2)/s (n = 7, s.c.)] were in agreement with values reported for tumours from patients with EOC, while the mean vascular signal fraction (VSF) was lower (≤ 4%), probably due to the more rapid growth of preclinical models. Both s.c. and i.p. xenografts are valuable preclinical models for monitoring biochemical and physiopathological changes associated with in vivo EOC tumour growth and response to therapy, which may serve as the basis for further clinical development of noninvasive MR approaches., (Copyright © 2011 John Wiley & Sons, Ltd.)

The development of molecular technologies, together with progressive sophistication of molecular imaging methods, has allowed the further elucidation of the multiple mutations and dysregulatory effects of pathways leading to oncogenesis. Acting against these pathways by specifically targeted agents represents a major challenge for current research efforts in oncology. As conventional anatomically based pharmacological endpoints may be inadequate to monitor the tumor response to these targeted treatments, the identification and use of more appropriate, noninvasive pharmacodynamic biomarkers appear to be crucial to optimize the design, dosage and schedule of these novel therapeutic approaches. An aberrant choline phospholipid metabolism and enhanced flux of glucose derivatives through glycolysis, which sustain the redirection of mitochondrial ATP to glucose phosphorylation, are two major hallmarks of cancer cells. This review focuses on the changes detected in these pathways by MRS in response to targeted treatments. The progress and limitations of our present understanding of the mechanisms underlying MRS-detected phosphocholine accumulation in cancer cells are discussed in the light of gene and protein expression and the activation of different enzymes involved in phosphatidylcholine biosynthesis and catabolism. Examples of alterations induced in the MRS choline profile of cells exposed to different agents or to tumor environmental factors are presented. Current studies aimed at the identification in cancer cells of MRS-detected pharmacodynamic markers of therapies targeted against specific conditional or constitutive cell receptor stimulation are then reviewed. Finally, the perspectives of present efforts addressed to identify enzymes of the phosphatidylcholine cycle as possible novel targets for anticancer therapy are summarized., (Copyright © 2011 John Wiley & Sons, Ltd.)

The C6 methylene protons were selectively detected in (1)H-NMR spectra of intact glioma cells incubated with 6-(13)C-D-2-deoxyglucose (6-(13)C-2dG), a (13)C-enriched glucose analog that is suitable for monitoring glucose utilization in brain tumors. Spectral editing via (1)H-(13)C scalar coupling was performed with twin spin-echo double resonance (T-SEDOR), a pulse sequence which combines chemical specificity and high sensitivity, requires no solvent pre-saturation, and can easily be adapted to imaging protocols. This work demonstrates the suitability of the pulse sequence for monitoring 6-(13)C-2dG uptake in living cells in vitro, in spite of line-broadening and the occurrence of other strong signals in the spectral region of interest (3.5-4.4 ppm)., (Copyright 2000 John Wiley & Sons, Ltd.)

More than 50% of cancers fail to respond to any individual treatment and tumour follow-up after treatment plays a major role in routine therapy planning and pharmacological research. Today, MRS is the only technological approach providing non-invasive access to tumour biochemistry. Ten years ago, expectations were raised concerning 31P MRS as an exciting and promising technical approach to the study of tumours. However the expectations have not always come to fruition. How close are we now to seeing routine 31P NMR in clinical oncology? This review of the 127 published papers shows spectroscopy results in more than 150 experimental animal tumour models. These tumour/host/treatment systems provide us with a useful basis to evaluate the current state of the art, summarize the basic knowledge presently available, determine the key points underlying the present disappointment of some clinical oncologists and stimulate new basic research. The information collected concerns the discussion of the reliability of experimental models in oncology, the technical improvement of magnetic resonance technology and the monitoring of bioenergetic status, pH regulation and phospholipid metabolism in treated and untreated tumours. Recent advances (two-thirds of the papers have been published in the last 5 years) seem to provide more optimistic perspectives than those generally accepted a few years ago, in the depressing period following early pioneering work.

1H NMR spin-lattice relaxation times (T1) were measured in vitro and in vivo in Friend leukemia cell tumors during subcutaneous tumor growth in syngeneic mice and after in vivo administration of either purified murine interferon alpha/beta (IFN) or recombinant tumor necrosis factor alpha (TNF). Untreated tumors exhibited monoexponential T1 relaxation independently of tumor age at least until Day 16 after implantation. Histological examinations showed that under these conditions tumors were highly homogeneous and substantially free of necrotic areas. Peritumoral administrations of either IFN or TNF did not significantly alter the tumor relaxation properties at early stages of inhibition of tumor growth. The longitudinal relaxation decay became instead clearly biexponential at later stages (more than 7 days of IFN treatment or 2 days after TNF administration). While the T1 relaxation behavior could be unequivocally correlated with the presence of necrotic areas in these tumors, it could not be considered as an early marker of the altered growth capability, induced by administration of either IFN or TNF.